Research Group Proteomics and Cancer Cell Signaling

Eukaryotic genes are divided into exons and introns ('split gene architecture') and are transcribed into pre-mRNA. Prior to translation, the introns must be precisely and efficiently removed and the exons ligated together in a process called pre-mRNA splicing, orchestrated by mRNA splicing factors and binding proteins, which is a fundamental process that occurs in all eukaryotic cells. We have recently discovered that mRNA splicing factors plays a key role in mediating drug response in cancer cells (Jayavelu AK. Nature 2020). We showed (non-mutated)-splicing factor regulation by phosphorylation could alter the response to targeted therapy in cancer. How splicing factors as a class are post-translationally regulated by signaling pathways remains unknown, and this understanding may reveal novel mechanisms and therapeutic opportunities. Thus the mechanism of mRNA splicing factors regulation in the context of various cancer relevant mutations and in different cancer entities, in particular hematological malignancies is one of the major foci of our work. Therefore we intend to systematically investigate the regulators and pathways that mediate post-translational modifications to control the function of splicing factors.

Drug resistance in cancer continues to be one of the principle limiting factors in achieving cure, and a major impediment to patient survival. This problem is aggravated due to its multifaceted nature: Cancer cell intrinsic and extrinsic environmental factors result in a diverse spectrum of responses to therapy. Understanding these factors is critical for improving therapeutic efficacy. It remains largely unclear what the key mutations in a given cancer are, and how they impact therapy outcome. Better knowledge of tumor proteome, the signaling pathways, signaling dependencies, offer unprecedented opportunities to understand and overcome drug resistance. Our recent discovery of a novel proteome subtype in acute myeloid leukemia with clinical relevance clearly support our notion (Jayavelu AK. Cancer Cell 2022). Advanced mass spectrometric (MS) approaches enable a systematic characterization of these components by capturing the dynamic behavior of proteins in an unbiased manner. Important questions in the area of cancer drug resistance and persistence comprise the understanding of the molecular signaling networks of cancer cells, how they adopt to drug exposure, what the essential cancer cell dependencies are and how they are regulated. Therefore, the overarching goal of our lab is to address these key questions in cancer entities such as leukemia and osteosarcoma by applying recent technological developments in high-sensitivity and high-throughput MS.

Towards this we develop and employ highly sensitive and high-throughput quantification methods to increase coverage and reproducibility. We developed a minimalistic approach to antibody based post-translational modified peptide enrichment coupled to MS, a novel workflow called EasyAb. It allows rapid, sensitive, high-throughput, and cost-effective enrichment of modified peptides that requires antibody Further we are actively developing high-throughput single cell proteome technology.

The three main themes of our lab

• Regulation of splicing factors in leukemia
• Drug resistance: Cell intrinsic and extrinsic factors in leukemia & osteosarcoma
• Development & application of single cell proteome technology

OUTLOOK

Our research and technology development aims to unravel novel mechanisms and signaling pathways essential in mediating cancer drug response. Such investigation will broaden our understanding of drug resistance mechanisms and aims to uncover novel therapeutic targets with the goal toward cancer cure. We utilize human & murine cell lines, primary patient samples, CRISPR technology, drug screen, and employ mouse models.

FOR THOSE WHO ARE INTERESTED IN OUR GROUP

We welcome applications for master, graduate, and post-doctoral positions. For post-doc we also encourage applications for external fellowships. We seek highly ambitious and motivated candidates who share our commitments to science and passion for interdisciplinary research in MS-technology, medicine, cancer biology, and systems biology or similar. Write to us: ak.jayavelu@dkfz-heidelberg.de

Lab members

Dr. Ashok Kumar Jayavelu (Group leader)
Noelle Jung (TA trainee)
Joris Maximilian Frenz (PhD student)
Lianghao Mao (MD student)
Yongjie Wang (Guest PhD student)
Dr.Lavanya Mokada Gopal (Post-Doctoral Researcher)
Thorben Hennig (Master student)
Marlene Adams (Bachelor student)

Selected publications

Jayavelu AK *, Wolf S*, Buettner F *,....Cox J, Brüne B, Röllig C, Thiede C, Steffen B, Bornhäuser M, Trumpp A, Urlaub H, Stegmaier K, Serve H#, Mann M# and Oellerich T#. The Proteogenomic Subtypes of Acute Myeloid Leukemia. Cancer Cell. 2022 Mar 14;40(3):301-317. * shared first-authors and # shared last authors.

Schnoeder TM, Schwarzer A, Jayavelu AK,....Mann M, Lane SW, Bullinger L, Ori A, Eyss BV, Bonifer C, Heidel F. Blood. 2021. PLCG1 is required for AML1-ETO leukemia stem cell self-renewal. Blood 2022. Feb 17;139 (7):1080-1097

Haider N*, Lebastchi J*, Jayavelu AK*, Batista TM, Pan H, Dreyfuss JM, Carcamo-Orive I, Knowles JW, Mann M, Kahn CR. Signaling defects associated with insulin resistance in nondiabetic and diabetic individuals and modification by sex. J Clin Invest. 2021. Nov 1;131(21).

Jayavelu AK, Schnöder TM, Perner F, Herzog C, Meiler A, Krishnamoorty G, Mohr J, , Kathner C, Stephan BE, Austin R, Brandt S, Palandri F, Odenwald K, Schröder N, Isermann B, Edlich F, Sinha AU, Ungelenk M, Hübner CA, Zeiser R, Jilg S, Jost PJ, Mullally A, Bullinger L, Mertens PR, Lane SW, Mann M# and Heidel FH#. Splicing factor Ybx1 maintains persistent Jak2-mutated neoplasms. Nature. 2020 Dec;588(7836):157-163.

Batista TM, Jayavelu AK, Albrechtsen NJW, Iovino S, Lebastchi J, Pan H, Dreyfuss J, Krook A, Zierath RJ, Mann M, Kahn RC. A Cell-Autonomous Signature of Dysregulated Protein Phosphorylation Underlies Muscle Insulin Resistance in Type 2 Diabetes. Cell Metabolism. 2020 Nov 3;32(5):844-859.