Biology subjects

Hoheisel, J. D.

Publications and source records attributed to Hoheisel, J. D..

3 recordsLinked to original sources

bioRxiv2025

Exploiting TGF-β-mediated Stromal Programming in Homologous Recombination-Deficient Pancreatic Cancer

The tumor microenvironment (TME) actively contributes to pancreatic ductal adenocarcinoma (PDAC) pathogenesis through dynamic bidirectional tumor-stroma interactions. Here, we demonstrate that homologous recombination-defective (HRD) tumor epithelium reprograms the TME in a genotype-specific manner to enhance cancer aggressiveness. Using genetically engineered mouse models, pancreatic stellate cell (PSC) and cancer-associated fibroblast (CAF) co-culture systems, single-nucleus multiomics, and human PDAC models, we show that tumoral loss of ATM serine/threonine kinase drives CAFs toward SMA+ myofibroblastic differentiation, independently of P53 status. These myCAFs, in turn, promote cancer aggressiveness and chemoresistance. Mechanistically, ATM deficiency increases reactive oxygen species and contractility signaling, enhancing TGF-{beta}1 secretion. Pharmacological TGF-{beta} inhibition reverses myCAF differentiation, sensitizes tumors to chemotherapy, and impairs tumor progression in both murine and human ATM-null models. Our findings reveal that ATM-deficient tumors shape a cancer-promoting niche via TGF-{beta} signaling and identify dual targeting of intrinsic and extrinsic vulnerabilities as a promising precision oncology strategy. SIGNIFICANCEHRD pancreatic cancers reprogram the tumor microenvironment in a genotype-specific manner through TGF-{beta}-driven myCAF-enrichment. Targeting this stromal axis alongside platinum-based chemotherapy improves therapeutic efficacy in ATM-deficient models. These findings highlight the need to integrate epithelial genotype and stromal context for truly personalized treatment strategies in PDAC.

cancer biology↗

bioRxiv2022

SOX2 dosage sustains tumor-promoting inflammation to drive disease aggressiveness by modulating the FOSL2/IL6 axis

BackgroundInflammation is undoubtedly a hallmark of cancer development. Its maintenance within tumors and subsequent consequences on disease aggressiveness is less understood. MethodsMulti-omic analyses of 27 (~ 5000 samples) entities from the TCGA, GEO and in-house data was performed to investigate the molecular determinant of tumor aggressiveness. Using molecular loss of function data, the mechanistic underpinnings of inflammation-induced tumor aggressiveness was addressed. ResultsThe data revealed a significant association between somatic copy number alterations (sCNA) and tumor aggressiveness, with amplification of the transcription factor SOX2 being the most important feature among novel and known aggressiveness-associated genes such as ZIC5 and MYEOV. Mechanistically, SOX2 regulates a group of aggressiveness-related genes including the AP1 transcription factor FOSL2 to sustain pro-inflammatory pathway such as IL6-JAK-STAT3, TNFA and IL17 signaling pathways. Prolonged inflammation induces immunosuppression and further leads to activation of cytidine deamination and consequential DNA damage evidenced by enrichment in cytidine deamination mutational signatures in aggressive tumors. The resulting DNA damage affects tumor suppressor genes such as TP53, which was the most mutated gene in aggressive tumors compared with less aggressive tumors (38% vs 14%), thereby releasing cell cycle control. This was exemplified in Glioblastoma multiform, where TP53 and IDH1 mutations are predominant. IDH1 mutations were almost only seen in younger patients (>45 years, > 90%) and may explain the previously reported favorable prognosis. ConclusionTaken together, our data demonstrate the implication of SOX2 in promoting DNA damage and genome instability by sustaining inflammation via FOSL2/IL6, resulting in tumor aggressiveness.

cancer biology↗

bioRxiv2021

Occurrence, functionality, and abundance of the TERT promoter mutations

Telomere shortening at chromosomal ends due to the constraints of the DNA replication process acts as a tumor suppressor by restricting the replicative potential in primary cells. Cancers evade that limitation primarily through the reactivation of telomerase via different mechanisms. Mutations within the promoter of the telomerase reverse transcriptase (TERT) gene represent a definite mechanism for the ribonucleic enzyme regeneration predominantly in cancers that arise from tissues with low rates of self-renewal. The promoter mutations cause a moderate increase in TERT transcription and consequent telomerase upregulation to the levels sufficient to delay replicative senescence but not prevent bulk telomere shortening and genomic instability. Since the discovery, a staggering number of studies and publications have resolved the discrete aspects, effects, and clinical relevance of the TERT promoter mutations. The promoter mutations link transcription of TERT with oncogenic pathways, associate with markers of poor outcome, and define patients with reduced survivals in several cancers. In this review, we discuss the occurrence and impact of the promoter mutations and highlight the mechanism of TERT activation. We further deliberate on the foundational question of the abundance of the TERT promoter mutations and a general dearth of functional mutations within noncoding sequences, as evident from pan-cancer analysis of the whole-genomes. We posit that the favorable genomic constellation within the TERT promoter may be less than a common occurrence in other noncoding functional elements. The evolutionary constraints limit the functional fraction within the human genome, hence the lack of abundant mutations outside the coding sequences.

cancer biology↗