Biology subjects

Akshinthala, D.

Publications and source records attributed to Akshinthala, D..

3 recordsLinked to original sources

bioRxiv2023

Establishing conditions for the generation and maintenance of estrogen receptor-positive organoid models of breast cancer

Patient-derived organoid models of estrogen receptor-positive (ER+) breast cancer would provide a much-needed tool to better understand drug resistance and disease progression. However, the establishment and long-term maintenance of ER expression, function, and response in vitro remains a significant challenge. Here, we report the development of an ER+ breast tumor organoid medium (BTOM-ER) that conserves ER expression, estrogen responsiveness, and dependence, as well as sensitivity to endocrine therapy of ER+ patient-derived xenograft organoids (PDXO). Our findings demonstrate the utility of subtype-specific culture conditions that better mimic the characteristics of the breast epithelial biology and microenvironment, providing a powerful platform for investigating therapy response and disease progression of ER+ breast cancer.

cancer biology↗

bioRxiv2020

Clonal expansion of personalized anti-tumor T cells from circulation using tumor organoid-immune co-cultures

Tumor-specific cytotoxic T cells are effective tools for cancer immunotherapy, but the ability to generate them continues to be a challenge. Furthermore, there are no compelling approaches to empirically identify tumor-targeting T cells and T cell receptors by exploiting the multitude of antigens on tumor cell surfaces. Here, we use patients peripheral blood and autologous tumor organoids to enrich tumor-specific cytotoxic T cells with patient-specific killing mechanisms and a tissue-resident memory phenotype. We further demonstrate that these organoid-primed T (opT) cells undergo several orders of magnitude of clonal expansion and express T cells receptors and check-point proteins unique to each patient. Importantly, transferring the TCRs to heterologous T cells was sufficient to confer tumor recognition in a patient-specific manner. Thus, we report a patient-specific and antigen-agnostic platform for expansion of tumor-targeting T cells and identification of cancer-targeting TCRs from the peripheral blood of pancreatic cancer patients that can be exploited for immunotherapy applications.

cancer biology↗

bioRxiv2019

Pancreatic tumor organoids for modeling in vivo drug response and discovering clinically-actionable biomarkers

Patient-derived models are transforming translational cancer research. It is not clear if the emergence of patient-derived organoid (PDO) models can extend the utility of the widely used patient-derived xenograft (PDX). In addition, the utility of PDO models for serum biomarker discovery is not known. Here, we demonstrate that PDO models recapitulate the genomics, cell biology, glycomics and drug responses observed in PDX models. Furthermore, we demonstrate the applicability of PDO models for identification of N-glycans that are enriched in the glycome of pancreatic ductal adenocarcinoma (PDAC). Surprisingly, among all the glycans observed in PDX and PDOs, a core set of 57 N-glycans represent 50-94% of the relative abundance of all N-glycans detected, suggesting that only a subset of glycans dominate the cell surface landscape in PDAC. In addition, we outline a tumor organoid-based pipeline to identify surface proteins in extracellular vesicles (EV) from media supernatant of PDO cultures. When combined with the affinity-based validation platform, the EV surface proteins discovered in PDOs are effective in differentiating patients with PDAC from those with benign pancreatitis in the clinic, identifying PDO as powerful discovery platform for serum biomarkers. Thus, PDOs extend the utility of the archival collections of PDX models for translational research and function as a powerful platform for identification of clinically-actionable biomarkers in patients blood. Significance statementTumor organoids extend the utility of PDX models as platforms for investigating drug response, glycosylation changes and function as new platforms for discovering blood-based biomarkers

cancer biology↗