Biology subjects

Khanna, P.

Publications and source records attributed to Khanna, P..

9 recordsLinked to original sources

bioRxiv2026

Shared somatosensory-motor neural population dynamics track motor recovery after stroke

SO_SCPLOWUMMARYC_SCPLOWAlthough somatosensation is known to be important for precise hand control, how coordinated activity across sensory and motor cortical areas supports hand movements and object interactions is unclear. We simultaneously recorded neural activity from dorsal premotor cortex (PMd) and Area 2 of the primary somatosensory cortex in three rhesus macaques performing a reach-to-grasp task during recovery from a primary motor cortex (M1) lesion. Using dual-area latent factor analysis, we decomposed population activity into cross-area factors (CFs) shared between PMd and Area 2 and within-area factors (WFs) local to each region. Shared CFs tracked hand kinematics closely despite explaining less overall variance. Strikingly, the emergence of long-timescale, stereotyped sensory-motor cross-area dynamics was correlated with recovery of prehension and object grasping, whereas changes in within-area dynamics were not correlated with recovery. These findings suggest that restoration of coordinated sensory-motor population dynamics is important for recovery of skilled hand function after injury.

neuroscience↗

bioRxiv2025

Detection and monitoring of translocation renal cell carcinoma via plasma cell-free epigenomic profiling

TFE3 translocation renal cell carcinoma (tRCC), an aggressive kidney cancer driven by TFE3 gene fusions, is frequently misdiagnosed owing to morphologic overlap with other kidney cancer subtypes. Conventional liquid biopsy assays that detect tumor DNA via somatic mutations or copy number alterations are unsuitable for tRCC, since it often lacks recurrent genetic alterations and because fusion breakpoints are highly variable between patients. We reasoned that epigenomic profiling could more effectively detect tRCC, because the driver fusion constitutes an oncogenic transcription factor that alters gene regulation. By defining a TFE3-driven epigenomic signature in tRCC cell lines and detecting it in patient plasma using chromatin immunoprecipitation and sequencing, we distinguished tRCC from clear cell RCC (AUC=0.87) and healthy controls (AUC=0.91) at low tumor fractions (<1%). This work establishes a framework for non-invasive epigenomic detection, diagnosis and monitoring of tRCC, with implications for other mutationally quiet, fusion-driven cancers. SIGNIFICANCETranslocation renal cell carcinoma (tRCC) is an aggressive fusion-driven subtype of kidney cancer that is frequently misdiagnosed due to morphologic overlap with other kidney cancer subtypes. Conventional liquid biopsy assays targeting DNA alterations are suboptimal for use in tRCC due to its paucity of genomic changes. We demonstrate the utility of cell-free chromatin profiling to noninvasively detect and monitor tRCC with high accuracy, a method that could have applicability to other genomically quiet cancers.

genomics↗

bioRxiv2025

Phenotypic screening converges on CDK9 inhibition as a therapeutic strategy in translocation renal cell carcinoma

Translocation renal cell carcinoma (tRCC) is an aggressive kidney cancer driven by gene fusions of the TFE3 transcription factor. TFE3 is essential in tRCC but dispensable in normal cells, presenting an attractive but pharmacologically challenging therapeutic target. We show that the basic helix-loop-helix (bHLH) domain of TFE3 is crucial for chromatin binding and transcriptional function. Via a phenotypic screen of 25,000 compounds, we identified molecules that either displace or retain chromatin-bound TFE3. BRD6866, a compound trapping TFE3 on chromatin, emerged as a pan-CDK inhibitor. Mechanistically, its inhibition of CDK9 - a key regulator of transcriptional elongation - was linked to impaired TFE3 fusion activity. These effects were recapitulated by the CDK9-selective inhibitor enitociclib, which downregulated TFE3 targets and suppressed tRCC cell growth. Our findings nominate CDK9 inhibition as a therapeutic strategy in tRCC and demonstrate the utility of mechanism-informed phenotypic screening for challenging targets.

cancer biology↗

bioRxiv2025

Dual Inhibition of CDK4/6 and mTORC1 Establishes a Preclinical Strategy for Translocation Renal Cell Carcinoma

PurposeTranslocation renal cell carcinoma (tRCC) is a rare and aggressive subtype of kidney cancer driven by an oncogenic fusion involving a transcription factor in the MiT/TFE gene family, most commonly TFE3. Treatment of tRCC currently lacks a clear standard of care, underscoring the pressing need to nominate new therapeutic targets with mechanistic rationale in this cancer. Experimental DesignIn this study, we applied integrative genomic approaches to identify activation of the cyclin-dependent kinase 4/6 (CDK4/6) and mammalian target of rapamycin complex 1 (mTORC1) pathways in tRCC. We tested the activity of CDK4/6 inhibitors (CDK4/6i), alone or in combination with mTORC1-selective inhibition, using in vitro and in vivo models of tRCC. ResultstRCC tumors displayed multiple genomic and transcriptional features associated with activation of the CDK4/6 and mTORC1 signaling pathways. Genetic or pharmacologic inhibition of CDK4/6 suppressed tRCC cell growth and induced cell cycle arrest in vitro but was not cytotoxic, with rapid cell regrowth observed after drug withdrawal. The mTORC1-selective inhibitor, RMC-5552, potently reduced translation of Cyclin D1, which complexes with CDK4/6 proteins to regulate G1-S cell cycle progression. Combined treatment with the CDK4/6 inhibitor, palbociclib, and RMC-5552 resulted in synergistic suppression of tRCC cell viability and increased markers of apoptosis in vitro. The combination of palbociclib and RMC-5552 in a tRCC xenograft model showed greater eOicacy than either single agent while also being well-tolerated. ConclusionsOur study indicates the therapeutic potential of combined CDK4/6 and mTORC1 inhibition in tRCC, providing the rationale for further clinical evaluation of this strategy. Translational RelevanceTranslocation renal cell carcinoma (tRCC) is a rare and aggressive form of kidney cancer that accounts for 2-5% of all RCCs in adults and around 50% of RCCs in children. tRCC lacks effective therapies and represents a significant unmet clinical need. Therapies approved for clear cell RCC (ccRCC), including VEGF/multikinase inhibitors and immune checkpoint blockade, typically show decreased efficacy in tRCC. Via an integrative genomic analysis, we nominate combined inhibition of the cyclin-dependent kinase 4/6 (CDK4/6) and mammalian target of rapamycin complex 1 (mTORC1) pathways in tRCC. We demonstrate that combining the CDK4/6 inhibitor palbociclib with the mTORC1-selective inhibitor RMC-5552 synergistically inhibits the growth of tRCC cells in vitro and of tRCC xenografts in vivo, where the combination is well-tolerated. This proof-of-concept study provides preclinical evidence supporting CDK4/6 inhibitor-based combination regimens tailored to tRCC biology, offering a foundation for future clinical studies in tRCC, which currently has no clear standard of care.

cancer biology↗

bioRxiv2025

Separable global and local beta burst dynamics in motor cortex of primates

Sensorimotor beta band oscillations are known to modulate during normal movement control and abnormal beta modulation is linked to pathological bradykinesia. However, the functional differences between beta localized to one brain area versus beta synchronized across brain areas remains unclear. We monitored beta bursts in non-human primates, both neurotypical and stroke- impaired, during the performance of complex motor tasks. Across both groups of animals, we identified two distinct beta burst types: global bursts that tend to be synchronized across cortical and subcortical areas, and local bursts that tend to be confined to cortex. These two types exhibited distinct neural dynamics, with global bursts linked to reduced firing variability and overall slowed movements. In contrast, local bursts often occurred during the execution of complex behaviors, particularly during prehension. We found evidence for changes in the distribution of global and local bursts during recovery after stroke. In impaired animals early after stroke, global bursts predominated and were associated with reduced speed and impaired grasping. Notably, recovery of grasping was associated with a reduction in global bursts and an increase in local bursts, suggesting that local bursts may play an important role during prehension. Our findings reveal distinct roles of global and local beta bursts and indicate that the normalization of global and local burst timing tracks recovery of dexterity.

neuroscience↗

bioRxiv2024

Exploring N6-Methyladenosine and long transcripts in glioma cells and extracellular vesicles.

N6-methyladenosine (m6A) is the most prevalent internal mRNA modification, enriched in the CNS yet poorly characterized in glioma. Using long-read RNA sequencing, we mapped m6A in an in vitro glioma model following knockdown (KD) of the reader IGF2BP2, writer METTL3, and eraser ALKBH5, with naive glioma cells and astrocytes as controls. Glioma cells exhibited a two-fold reduction in global m6A, suggesting progressive loss from healthy to malignant states. Integrated analysis revealed that m6A mediated control of gene expression is influenced by modification topology (CDS:3'UTR), transcript biotype, and length. Regulator KD, particularly ALKBH5 induced redistribution of m6A toward 3'UTR with consequent gene upregulation. We also identified m6A-mediated isoform switching, with a higher usage of retained intron and nonsense-mediated decay isoforms. Structural and splicing alterations at the isoform level were identified unique to each KD condition indicating m6A driven aberrant alternative splicing. At the functional level, KD specific remodeling of oncogenic signaling was also observed. ALKBH5 KD suppressed MYC targets and pro-apoptotic signaling while METTL3 KD enhanced mTOR and PI3K-AKT signaling. Collectively, these results demonstrate that m6A mediated regulation in glioma is highly context-dependent, defining distinct clinically relevant phenotypes. This has implications for future biomarker discovery and development of targeted therapeutics.

cancer biology↗

bioRxiv2024

TFE3 fusions direct an oncogenic transcriptional program that drives OXPHOS and unveils vulnerabilities in translocation renal cell carcinoma

Translocation renal cell carcinoma (tRCC) is an aggressive subtype of kidney cancer driven by TFE3 gene fusions, which act via poorly characterized downstream mechanisms. Here we report that TFE3 fusions transcriptionally rewire tRCCs toward oxidative phosphorylation (OXPHOS), contrasting with the highly glycolytic metabolism of most other renal cancers. This TFE3 fusion-driven OXPHOS program, together with heightened glutathione levels found in renal cancers, renders tRCCs sensitive to reductive stress - a metabolic stress state induced by an imbalance of reducing equivalents. Genome-scale CRISPR screening identifies tRCC-selective vulnerabilities linked to this metabolic state, including EGLN1, which hydroxylates HIF-1 and targets it for proteolysis. Inhibition of EGLN1 compromises tRCC cell growth by stabilizing HIF-1a and promoting metabolic reprogramming away from OXPHOS, thus representing a vulnerability to OXPHOS-dependent tRCC cells. Our study defines a distinctive tRCC-essential metabolic program driven by TFE3 fusions and nominates EGLN1 inhibition as a therapeutic strategy to counteract fusion-induced metabolic rewiring.

cancer biology↗

bioRxiv2023

SOX4-SMARCA4 complex promotes glycolysis-dependent TNBC cell growth through transcriptional regulation of Hexokinase 2

Tumor cells rely on increased glycolytic capacity to promote cell growth and progression. While glycolysis is known to be upregulated in the majority of triple negative (TNBC) or basal-like subtype breast cancers, the mechanism remains unclear. Here, we used integrative genomic analyses to identify a subset of basal-like tumors characterized by increased expression of the oncogenic transcription factor SOX4 and its co-factor the SWI/SNF ATPase SMARCA4. These tumors are defined by unique gene expression programs that correspond with increased tumor proliferation and activation of key metabolic pathways, including glycolysis. Mechanistically, we demonstrate that the SOX4-SMARCA4 complex mediates glycolysis through direct transcriptional regulation of Hexokinase 2 (HK2) and that aberrant HK2 expression and altered glycolytic capacity are required to mediate SOX4-SMARCA4-dependent cell growth. Collectively, we have defined the SOX4-SMARCA4-HK2 signaling axis in basal-like breast tumors and established that this axis promotes metabolic reprogramming which is required to maintain tumor cell growth.

cancer biology↗

bioRxiv2021

The brain uses invariant dynamics to generalize outputs across movements

It has been proposed that the nervous system has the capacity to generate a wide variety of movements because it re-uses some invariant code. Previous work has identified that dynamics of neural population activity are similar during different movements, where dynamics refer to how the instantaneous spatial pattern of population activity changes in time. Here we test whether invariant dynamics of neural populations are actually used to issue the commands that direct movement. Using a brain-machine interface that transformed rhesus macaques motor cortex activity into commands for a neuroprosthetic cursor, we discovered that the same command is issued with different neural activity patterns in different movements. However, these different patterns were predictable, as we found that the transitions between activity patterns are governed by the same dynamics across movements. These invariant dynamics are low-dimensional, and critically, they align with the brain-machine interface, so that they predict the specific component of neural activity that actually issues the next command. We introduce a model of optimal feedback control that shows that invariant dynamics can help transform movement feedback into commands, reducing the input that the neural population needs to control movement. Altogether our results demonstrate that invariant dynamics drive commands to control a variety of movements, and show how feedback can be integrated with invariant dynamics to issue generalizable commands.

neuroscience↗