Rushika Perera, PhD

Assistant Professor
Department of Anatomy
rushika.perera@ucsf.edu

How do cancer cells escape tightly controlled regulatory circuits that link their growth to extracellular signaling cues? An emerging theme in cancer biology is how, in addition to genetic alterations in signaling pathways (eg. MAPK and PI3K), cancer cells can hijack normal stress response pathways to overcome strict reliance on external nutrients for growth. Pancreatic adenocarcinoma (PDA) is the quintessence of an aggressive malignancy that thrives in nutrient poor, hypoxic environments, by systemtically altering the core pathways for nutrient acquisition and utilization. These alterations include increased uptake of glucose and glutamine, along with constitutive activation of scavenging pathways that converge at the lysosome, namely autophagy (cellular self-catabolism) and macropinocytosis (bulk uptake of extracellular material).

In our lab we study the cancer-specific mechanisms of autophagy-lysosome activation, and how this organellar system contributes to metabolic reprogramming in PDA. We hypothesize that the functional interplay between enhanced cellular trafficking pathways and activation of gene programs that regulate organelle dynamics and function is an essential, previously unrecognized mechanism for tumor growth. Our studies at the intersection of cell biology and cancer research aims to provide insight into how fundamental cellular process are rewired in cancer while also identifying new nodes for anti-cancer therapy.

We recently showed that the MiT/TFE family transcription factors (MITF, TFE3 and TFEB) are essential regulators of autophagy-lysosome activation in PDA. These proteins orchestrate transcriptional control of the biogenesis and function of the autophagosome-lysosome system and are required for maintenance of organelle integrity and metabolic homeostasis in PDA cells.

Building on these findings, we are interested in understanding in greater detail the regulatory circuits controlling sustained autophagy induction both at the transcriptional and signaling levels in PDA cells. How are the expression levels of MiT/TFE factors regulated? How do PDA cells bypass signaling that function to suppress MiT/TFE activity? How do PDA cells utilize basic nutrients derived from lysosomal catabolism to fuel their aberrant growth and metabolism? By using a combination of biochemistry, fluorescence imaging and proteomics in PDA cell lines, mouse models and primary patient derived cultures we aim to gain greater insight into these intriguing questions and make strides toward novel therapeutic approaches in cancer.

Primary Thematic Area: 
Cancer Biology & Cell Signaling
Secondary Thematic Area: 
Tissue / Organ Biology & Endocrinology
Research Summary: 
Autophagy: Organelle dynamics and metabolic reprogramming in pancreatic cancer

Websites

Publications: 

Beige Adipocyte Maintenance Is Regulated by Autophagy-Induced Mitochondrial Clearance.

Cell metabolism

Altshuler-Keylin S, Shinoda K, Hasegawa Y, Ikeda K, Hong H, Kang Q, Yang Y, Perera RM, Debnath J, Kajimura S

The Lysosome as a Regulatory Hub.

Annual review of cell and developmental biology

Perera RM, Zoncu R

Transcriptional control of autophagy-lysosome function drives pancreatic cancer metabolism.

Nature

Perera RM, Stoykova S, Nicolay BN, Ross KN, Fitamant J, Boukhali M, Lengrand J, Deshpande V, Selig MK, Ferrone CR, Settleman J, Stephanopoulos G, Dyson NJ, Zoncu R, Ramaswamy S, Haas W, Bardeesy N

YAP Inhibition Restores Hepatocyte Differentiation in Advanced HCC, Leading to Tumor Regression.

Cell reports

Fitamant J, Kottakis F, Benhamouche S, Tian HS, Chuvin N, Parachoniak CA, Nagle JM, Perera RM, Lapouge M, Deshpande V, Zhu AX, Lai A, Min B, Hoshida Y, Avruch J, Sia D, Campreciós G, McClatchey AI, Llovet JM, Morrissey D, Raj L, Bardeesy N