Molecularly targeted therapies aim to obstruct cell autonomous programs required for tumor growth. We show that mitogen-activated protein kinase (MAPK) and cyclin-dependent kinase 4/6 inhibitors act in combination to suppress the proliferation of KRAS-mutant lung cancer cells while simultaneously provoking a natural killer (NK) cell surveillance program leading to tumor cell death. The drug combination, but neither agent alone, promotes retinoblastoma (RB) protein-mediated cellular senescence and activation of the immunomodulatory senescence-associated secretory phenotype (SASP). SASP components tumor necrosis factor-α and intercellular adhesion molecule−1 are required for NK cell surveillance of drug-treated tumor cells, which contributes to tumor regressions and prolonged survival in a KRAS-mutant lung cancer mouse model. Therefore, molecularly targeted agents capable of inducing senescence can produce tumor control through non−cell autonomous mechanisms involving NK cell surveillance.

Autophagy, a cellular self-eating mechanism, is important for maintaining cell survival and tissue homeostasis in various stressed conditions. Although the molecular mechanism of autophagy induction has been well studied, how cells terminate autophagy process remains elusive. Here, we show that ULK1, a serine/threonine kinase critical for autophagy initiation, is a substrate of the Cul3-KLHL20 ubiquitin ligase. Upon autophagy induction, ULK1 autophosphorylation facilitates its recruitment to KLHL20 for ubiquitination and proteolysis. This autophagy-stimulated, KLHL20-dependent ULK1 degradation restrains the amplitude and duration of autophagy. Additionally, KLHL20 governs the degradation of ATG13, VPS34, Beclin-1, and ATG14 in prolonged starvation through a direct or indirect mechanism. Impairment of KLHL20-mediated regulation of autophagy dynamics potentiates starvation-induced cell death and aggravates diabetes-associated muscle atrophy. Our study identifies a key role of KLHL20 in autophagy termination by controlling autophagy-dependent turnover of ULK1 and VPS34 complex subunits and reveals the pathophysiological functions of this autophagy termination mechanism.

Tissue damage increases cancer risk through poorly understood mechanisms 1 . In the pancreas, pancreatitis associated with tissue injury collaborates with activating mutations in the Kras oncogene to dramatically accelerate the formation of early neoplastic lesions and ultimately pancreatic cancer 2 , 3 . By integrating genomics, single-cell chromatin assays and spatiotemporally-controlled functional perturbations in autochthonous mouse models, we show that the combination of Kras mutation and tissue damage promotes a unique chromatin state in the pancreatic epithelium that distinguishes neoplastic transformation from normal regeneration and is selected for throughout malignant evolution. This cancer-associated epigenetic state emerges within 48 hours of pancreatic injury, and involves an acinar-to-neoplasia ‘chromatin switch’ that contributes to the early dysregulation of genes defining human pancreatic cancer. Among the genes most rapidly activated upon tissue damage in the pre-malignant pancreatic epithelium is the alarmin cytokine IL-33, which cooperates with mutant Kras in unleashing the epigenetic remodeling program of early neoplasia and neoplastic transformation in the absence of injury. Collectively, our study demonstrates how gene-environment interactions can rapidly produce gene regulatory programs that dictate early neoplastic commitment and provides a molecular framework for understanding the interplay between genetics and environmental cues in cancer initiation.

SUMMARY Despite the development of second-generation antiandrogens, acquired resistance to hormone therapy remains a major challenge in treating advanced prostate cancer. We find that cancer-associated fibroblasts (CAFs) can promote antiandrogen resistance in mouse models and in prostate organoid cultures. We identify neuregulin 1 (NRG1) in CAF supernatant, which promotes resistance in tumor cells through activation of HER3. Pharmacological blockade of the NRG1/HER3 axis using clinical-grade blocking antibodies re-sensitizes tumors to hormone deprivation in vitro and in vivo . Furthermore, patients with castration-resistant prostate cancer with increased tumor NRG1 activity have an inferior response to second-generation antiandrogen therapy. This work reveals a paracrine mechanism of antiandrogen resistance in prostate cancer amenable to clinical testing using available targeted therapies.

A nine-layer WS/MoS heterostructure is established on a sapphire substrate after sequential growth of large-area and uniform five- and four-layer MoS and WS films by using sulfurization of predeposited 1.0 nm molybdenum (Mo) and tungsten (W), respectively. By using the results obtained from the ultraviolet photoelectron spectroscopy and the absorption spectrum measurements of the standalone MoS and WS samples, a type-II band alignment is predicated for the WS/MoS heterostructure. Increasing drain currents and enhanced field-effect mobility value of the transistor fabricated on the heterostructure suggested that a channel with higher electron concentration compared with the standalone MoS transistor channel is obtained with electron injection from WS to MoS under thermal equilibrium. Selective 2D crystal growth with (I) blank sapphire substrate, (II) standalone MoS, (III) WS/MoS heterostructure, and (IV) standalone WS was demonstrated on a single sapphire substrate. The results have revealed the potential of this growth technique for practical applications.