Biology subjects

Somarelli, J.

Publications and source records attributed to Somarelli, J..

3 recordsLinked to original sources

bioRxiv2021

KLF4 induces Mesenchymal-Epithelial Transition (MET) by suppressing multiple EMT-inducing transcription factors

Epithelial-Mesenchymal Plasticity (EMP) refers to reversible dynamic processes where cells can transition from epithelial to mesenchymal (EMT) or from mesenchymal to epithelial (MET) phenotypes. Both these processes are modulated by multiple transcription factors acting in concert. While EMT-inducing transcription factors (TFs) - TWIST1/2, ZEB1/2, SNAIL1/2/3, GSC, FOXC2 - are well-characterized, the MET-inducing TFs are relatively poorly understood (OVOL1/2, GRHL1/2). Here, using mechanism-based mathematical modeling, we show that the transcription factor KLF4 can delay the onset of EMT by suppressing multiple EMT-TFs. Our simulations suggest that KLF4 overexpression can promote phenotypic shift toward a more epithelial state, an observation suggested by negative correlation of KLF4 with EMT-TFs and with transcriptomic based EMT scoring metrics in cancer cell lines. We also show that the influence of KLF4 in modulating EMT dynamics can be strengthened by its ability to inhibit cell-state transitions at an epigenetic level. Thus, KLF4 can inhibit EMT through multiple parallel paths and can act as a putative MET-TF. KLF4 associates with patient survival metrics across multiple cancers in a context-specific manner, highlighting the complex association of EMP with patient survival.

cancer biology↗

bioRxiv2020

A cross-species drug discovery pipeline to identify and validate new treatments for osteosarcoma

PurposeOsteosarcoma is a rare but aggressive bone cancer that occurs primarily in children. Like other rare cancers, treatment advances for osteosarcoma have stagnated, with little improvement in survival for the past several decades. Developing new treatments has been hampered by extensive genomic heterogeneity and limited access to patient samples to study the biology of this complex disease. Experimental designTo overcome these barriers, we combined the power of comparative oncology with patient-derived models of cancer and high-throughput chemical screens in a cross-species drug discovery pipeline. ResultsCoupling in vitro high-throughput drug screens on low-passage and established cell lines with in vivo validation in patient-derived xenografts we identify the proteasome and CRM1 nuclear export pathways as therapeutic sensitivities in osteosarcoma, with dual inhibition of these pathways inducing synergistic cytotoxicity. ConclusionsThese collective efforts provide an experimental framework and set of new tools for osteosarcoma and other rare cancers to identify and study new therapeutic vulnerabilities.

cancer biology↗

bioRxiv2020

Convergent evolution of p38/MAPK activation in hormone resistant prostate cancer mediates pro-survival, immune evasive, and metastatic phenotypes

Adaptation of cancer cells to targeted therapy follows ecological paradigms observed in natural populations that encounter resource depletion and changing environments, including activation of pro-survival mechanisms, migration to new locations, and escape of predation. We identified the p38 MAPK pathway as a common molecular driver of these three responses during the adaptation to hormone therapy resistance in prostate cancer. The p38 pathway is activated in therapy-resistant cells and mechanistically drives these three convergent responses through sustained AR activity, enhanced invasion and metastasis, and immune evasion. Targeting p38 signaling may represent a new therapeutic strategy to treat men with metastatic, hormone therapy-resistant prostate cancer.

cancer biology↗