Biology subjects

Guda, K.

Publications and source records attributed to Guda, K..

3 recordsLinked to original sources

bioRxiv2021

SYS-Mut: Decoding the Functional Significance of Rare Somatic Mutations in Cancer

Current tailored-therapy efforts in cancer are largely focused on a small number of highly recurrently-mutated driver genes but therapeutic targeting of these oncogenes remains challenging. On the other hand, the vast number of genes mutated infrequently across cancers have received less attention, in part, due to a lack of understanding of their biologic significance. Here we present SYS-Mut, a systems biology platform that can robustly infer the biologic consequences of somatic mutations by integrating routine multi-omic profiles in primary tumors. We established the accuracy of SYS-Mut by recapitulating the functional impact of known driver genes in PanCancer datasets. Subsequent application of SYS-Mut on low-frequency gene mutations in Head and Neck Cancers (HNSC), followed by molecular and pharmacogenetic validation, revealed the lipidogenic network as a novel therapeutic vulnerability in aggressive HNSC. SYS-Mut is thus a robust scalable framework that enables discovery of new targetable avenues in cancer.

cancer biology↗

bioRxiv2021

Caveolin-3 Null Mutation in Family with Barretts Esophagus and Esophageal Adenocarcinoma

ObjectiveBarretts esophagus and esophageal adenocarcinoma demonstrate familial aggregation. The goal was to identify a segregating genetic variant in an large family and subsequently localize esophageal gene expression. MethodsWhole exome sequencing of genomic DNA from affected members of a large family with Barretts esophagus and esophageal adenocarcinoma was analyzed to identify rare coding variants in genes segregating with disease. Histopathological assessment of archived formalin fixed esophageal human and porcine tissues to localize expression of identified genes in esophagus. ResultsA segregating nonsense mutation in the gene Caveolin-3 (CAV3) was identified. Esophageal CAV3 localized to myoepithelial cells around esophageal submucosal glands. Histologic examination of a formalin fixed paraffin embedded esophagectomy specimen from an individual carrying the CAV3 null mutation revealed submucosal glands demonstrating atypical acinar metaplasia with absence of myoepithelial cells and no CAV3+ cells. ConclusionsSubmucosal glands contribute to healing of injured squamous esophagus. We theorize the truncating nonsense CAV3 mutation disrupts normal squamous healing and the organization of submucosal glands, making affected family members susceptible to the proliferation and development of metaplastic columnar Barretts esophagus.

genetics↗

bioRxiv2021

The EphB2-MYC Axis is a Major Determinant of Barrett's Pathobiology and a Therapeutic Vulnerability in Esophageal Cancer

Esophageal adenocarcinoma (EAC), a highly aggressive cancer with limited therapeutic options, often arises in the backdrop of a molecularly-complex esophageal metaplasia disorder, Barretts Esophagus (BE). Using transcriptomics and systems biology analyses of treatment-naive malignant/pre-malignant biopsy tissues, we found Eph receptor B2 (EphB2) tyrosine kinase signaling to be frequently hyperactivated during early stages of EAC development, and across the BE-EAC continuum. Functional studies revealed EphB2 to be an upstream post-translational regulator of c-MYC activity and as a key molecular dependency in BE/EAC. Single-cell transcriptomics in a porcine esophageal 3D spheroid model showed enhanced EphB2 and MYC activity to be significantly associated with BE-like cell fate. shRNA-based knockdown of EphB2 or small molecule inhibitors of MEK, that modulate MYC protein stability, proved effective in suppressing EAC tumor growth in vivo. These findings point to EphB2-MYC axis as an early promoter of EAC and a novel therapeutic vulnerability in this increasingly-prevalent esophageal malignancy. STATEMENT OF SIGNIFICANCEWe identify EphB2 signaling as a potential master regulator and early promoter of esophageal adenocarcinoma, and the proto-oncogene MYC as a key downstream effector of EphB2 function. Targeting the EphB2-MYC axis could be a promising therapeutic strategy for these often refractory and lethal EAC tumors.

cancer biology↗