Sandy Balkaran

Abstract As cancers progress, they become increasingly aggressive—metastatic tumours are less responsive to first-line therapies than primary tumours, they acquire resistance to successive therapies and eventually cause death 1,2 . Mutations are largely conserved between primary and metastatic tumours from the same patients, suggesting that non-genetic phenotypic plasticity has a major role in cancer progression and therapy resistance 3–5 . However, we lack an understanding of metastatic cell states and the mechanisms by which they transition. Here, in a cohort of biospecimen trios from same-patient normal colon, primary and metastatic colorectal cancer, we show that, although primary tumours largely adopt LGR5 + intestinal stem-like states, metastases display progressive plasticity. Cancer cells lose intestinal cell identities and reprogram into a highly conserved fetal progenitor state before undergoing non-canonical differentiation into divergent squamous and neuroendocrine-like states, a process that is exacerbated in metastasis and by chemotherapy and is associated with poor patient survival. Using matched patient-derived organoids, we demonstrate that metastatic cells exhibit greater cell-autonomous multilineage differentiation potential in response to microenvironment cues compared with their intestinal lineage-restricted primary tumour counterparts. We identify PROX1 as a repressor of non-intestinal lineage in the fetal progenitor state, and show that downregulation of PROX1 licenses non-canonical reprogramming.

Abstract Metastasis is the principal cause of cancer death, yet we lack an understanding of metastatic cell states, their relationship to primary tumor states, and the mechanisms by which they transition. In a cohort of biospecimen trios from same-patient normal colon, primary and metastatic colorectal cancer, we show that while primary tumors largely adopt LGR5 + intestinal stem-like states, metastases display progressive plasticity. Loss of intestinal cell states is accompanied by reprogramming into a highly conserved fetal progenitor state, followed by non-canonical differentiation into divergent squamous and neuroendocrine-like states, which is exacerbated by chemotherapy and associated with poor patient survival. Using matched patient-derived organoids, we demonstrate that metastatic cancer cells exhibit greater cell-autonomous multilineage differentiation potential in response to microenvironment cues than their intestinal lineage-restricted primary tumor counterparts. We identify PROX1 as a stabilizer of intestinal lineage in the fetal progenitor state, whose downregulation licenses non-canonical reprogramming.

Despite advances in therapy, Waldenstrom's macroglobulinemia (WM) remains incurable. Guidelines on therapeutic alternatives in WM recommended the use of alkylating agents, rituximab, nucleoside analogues and anthracyclins either in first line or at relapse and in combination in fit patients. While the overall response rates of combination regimens reached up to 80 - 90% in some studies, the complete response rate is low, no greater than 10 - 20%; and the disease-related median survival for symptomatic patients is approximately 6 years. As such, new therapeutic agents are needed for the treatment of WM. In ongoing efforts, advances were made in the understanding of the biology of WM so as to better target therapeutics for this malignancy. Several preclinical studies have demonstrated that the NFkappaB pathway is a potential target for therapeutics in WM. Bortezomib (Velcade) is the first approved proteasome inhibitor for treating relapse/refractory multiple myeloma and, among other mechanisms of action, significantly inhibits the NFkB pathway. This report provides an update on biological studies and clinical efforts to develop bortezomib as a new treatment of Waldenstrom's macroglobulinemia.