Biology subjects

Welte, L.

Publications and source records attributed to Welte, L..

6 recordsLinked to original sources

bioRxiv2026

Targeting AXL Overcomes Adaptive Resistance to KRAS Inhibition in KRAS-Driven Cancer

Direct KRAS inhibitors have established mutant KRAS as a clinically actionable target, yet adaptive resistance remains a major barrier to durable responses. To identify therapeutically actionable resistance mechanisms, we performed an unbiased in vivo CRISPR activation screen in an autochthonous lung adenocarcinoma model, identifying the receptor tyrosine kinase AXL as a dominant adaptive resistance driver. Pharmacologic AXL inhibition enhanced the efficacy of both allele-specific inhibition and the RAS(ON) multi-selective inhibitor daraxonrasib across lung and pancreatic cancer models, resulting in deeper and more durable suppression of MAPK signaling and improved tumor control. Beyond tumor-intrinsic effects, combined KRAS and AXL inhibition remodeled the tumor immune microenvironment, promoting an IFN{gamma}-responsive program, increased recruitment of cytotoxic T cells and sensitization to FAS-mediated apoptosis. Collectively, our findings identify AXL as a convergence point for adaptive resistance to KRAS inhibition and provide a mechanistically informed combination strategy to extend the durability of KRAS-directed therapies. Statement of SignificanceAn unbiased in vivo functional (CRISPR activation) screen identifies AXL as a convergence point for adaptive resistance to KRAS inhibition. By integrating adaptive response to KRAS inhibition with anti-tumor immunity, AXL represents a mechanistically actionable vulnerability whose inhibition deepens and prolongs responses to both allele-specific and pan-KRAS-targeted therapies.

cancer biology↗

bioRxiv2024

Acute Myeloid Leukemia with deletion 5q is an epigenetically distinct subgroup defined by heterozygous loss of KDM3B

Acute myeloid leukemia (AML) is a hematological malignancy characterized by a block in differentiation and accelerated proliferation of myeloid progenitor cells. Genes encoding for epigenetic regulators are among the most frequent targets for mutations and structural variations in AML, giving rise to profound epigenetic heterogeneity between and within tumors. Deletions of chromosome 5q [del(5q)] are among the most common copy number alterations in AML and are associated with extremely poor clinical outcome and therapy resistance, however the mechanisms linking del(5q) to leukemic progression are not understood. Analyzing DNA methylation profiles from 477 elderly AML patients using DNA methylome deconvolution, we discovered that del(5q) AML is an epigenetically distinct subgroup characterized by a signature of DNA hypermethylation, which we propose may be linked to dysregulation of H3K9me1/2 and overexpression of the leukemic stem cell marker, DNMT3B. Interrogation of the minimally deleted 5q region highlighted the H3K9me1/2 demethylase KDM3B as a likely target for haploinsufficiency in this subgroup. Our data suggest that del(5q) AML should be reconsidered as an epigenetically dysregulated subgroup, driven by heterozygous loss of KDM3B, and that the resulting imbalance of H3K9me1/2 may contribute to the progression of these aggressive leukemias.

cancer biology↗

bioRxiv2024

The influence of talus size and shape on in vivo talocrural hopping kinematics

Talus implants often come in standard sizes and shapes; however, humans vary in their bone size and shape. Consequently, patient-specific implants are becoming available. Understanding how shape changes alter function in a healthy cohort may help designers determine how much specificity is required in talocrural implants. Nine participants (5 females) hopped on one leg while biplanar video radiography and force plate data were collected. 3D bone models were created from computed tomography scans. Helical axes of motion were calculated for the talus relative to the tibia (rotation axes) and a cylinder was fit through the talar dome (morphological axis). Bland-Altman plots and spatial angles tested whether the rotation and morphological axes agree. A shape model of 36 (15 females) participants was established and a cylinder fit was morphed through the range of {+/-}3 standard deviations. The rotation and morphological axes largely agree regarding their orientation and location during hopping. The morphological axis consistently overestimates the orientation-component in anterior-posterior direction. Some shape components affect talar dome orientation and curvature independent of size. This suggests that besides size, the shape of the talar dome might affect the movement pattern during locomotion. Our findings are important to inform talocrural joint arthroplasty design.

bioengineering↗

bioRxiv2023

Reassessing the role of foot power in human gait

The foot acts as the primary interface to the ground during bipedal locomotion. It absorbs and returns energy over stance as the longitudinal arch deforms and recoils. The term arch recoil evokes the concept that the foots returned energy directly propels the centre of mass forward by lifting the talus. However, recent work has shown that arch recoil does not directly drive the body forward; instead, it lowers and posteriorly tilts the talus, putting it into a more favourable position for upright gait. Here, we aim to supply a kinetic explanation for this mechanism. We applied the unified deformable power approach to highly accurate talus kinematics from biplanar videoradiography and force plate measurements to measure the power absorbed/produced by the foot. We coupled these measurements with a simple mathematical model that allowed us to restrict rotation and linear actuation of the talus caused by the recoil of the arch to demonstrate that positive foot power primarily contributes to posteriorly tilting the talus. This suggests the role of positive foot power during propulsion is to keep the talocrural surface in a more favourable position for upright gait rather than directly propelling the centre of mass forwards. These findings highlight that arch mobility during push-off is critical for allowing the ankle to directly propel the body forward and upward during the propulsive phase of gait.

physiology↗

bioRxiv2023

It is all about the talus - In vivo tarsal joint complex kinematics during walking, running, and hopping

The interaction among joints of the midtarsal complex and subtalar joint is essential role for locomotor function; however, its complexity poses substantial challenges in quantifying their motions. We determine the mobility of these joints across locomotion tasks and investigate their alignment with individual talus morphology. Utilizing highly accurate biplanar videoradiography, three-dimensional bone kinematics were captured during walking, running, and hopping. We calculated the axis of rotation of each midtarsal and subtalar joint for the landing and push-off phases, respectively. A comparison was made between these rotation axes and the morphological subtalar axis. Measurement included total rotation about, the orientation of the rotation axes in the direction of the subtalar joint and its deviation via spatial angles for both phases. The rotation axes of all three bones relative to the talus closely align with the morphological subtalar axis. This suggests that the midtarsal and subtalar joints motions might be described by one commonly oriented axis. Despite having such axis, the location of axes and ranges of motion differed among the bones. Our results provide a novel perspective of healthy foot function across different sagittal plane-dominant locomotion tasks underscoring the importance of midtarsal and subtalar motion with respect to subject-specific talus morphology.

bioengineering↗

bioRxiv2022

Mobility of the human foot's medial arch enables upright bipedal locomotion

Developing the ability to habitually walk and run upright on two feet is one of the most significant transformations to have occurred in human evolution. Many musculoskeletal adaptations enabled bipedal locomotion, including dramatic structural changes to the foot and, in particular, the evolution of an elevated medial arch (H. Elftman and Manter, 1935). The foots arched structure has previously been assumed to play a central role in directly propelling the centre of mass forward and upward through leverage about the toes (Herbert Elftman and Manter, 1935) and a spring-like energy recoil (Hicks, 1955). Paradoxically, these roles seemingly require either arch rigidity (for the former) or mobility (for the latter). However, it is unclear whether or how the mobility and height of the medial arch support its propulsive lever function. Here we show, using high-speed biplanar x-ray, that regardless of intraspecific differences in medial arch height, arch recoil enables a longer contact time and favourable propulsive conditions for walking upright on an extended leg. This mechanism presumably helped drive the evolution of the longitudinal arch after our last common ancestor with chimpanzees, who lack this mobility during push-off. We discovered that the previously overlooked navicular-medial cuneiform joint is primarily responsible for this mobility in human arches, suggesting that future morphological investigations of this joint will provide new interpretations of the fossil record. Our work further suggests that enabling the mobility of the longitudinal arch in footwear and surgical interventions is critical for maintaining the ankles natural propulsive ability.

physiology↗